rs4963051

Variant names:

• chr11-1243735-G-A
• rs4963051
• NM_002458.3:c.6855G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002458.3(MUC5B):​c.6855G>A​(p.Thr2285Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,602,934 control chromosomes in the GnomAD database, including 24,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2030 hom., cov: 30)
  • Exomes 𝑓: 0.17 (22961 hom.)
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.76
• Publications: 3 publications found

Genes affected

MUC5B (HGNC:7516): (mucin 5B, oligomeric mucus/gel-forming) This gene encodes a member of the mucin family of proteins, which are highly glycosylated macromolecular components of mucus secretions. This family member is the major gel-forming mucin in mucus. It is a major contributor to the lubricating and viscoelastic properties of whole saliva, normal lung mucus and cervical mucus. This gene has been found to be up-regulated in some human diseases, including sinus mucosa of chronic rhinosinusitis (CRS), CRS with nasal polyposis, chronic obstructive pulmonary disease (COPD) and H. pylori-associated gastric disease, and it may be involved in the pathogenesis of these diseases. [provided by RefSeq, Jul 2010]

MUC5B-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-1243735-G-A is Benign according to our data. Variant chr11-1243735-G-A is described in ClinVar as Benign. ClinVar VariationId is 403142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.6855G>A	p.Thr2285Thr	synonymous	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-1097C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.6855G>A	p.Thr2285Thr	synonymous	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-1097C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24270 AN: 151428 Hom.: 2028 Cov.: 30

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.146 AC: 36308 AN: 248502 AF XY: 0.151

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.0814

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.00317

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.170 AC: 246445 AN: 1451388 Hom.: 22961 Cov.: 146 AF XY: 0.170 AC XY: 122542 AN XY: 722370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.150 AC: 4992 AN: 33238

American (AMR) AF: 0.0857 AC: 3830 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3876 AN: 26088

East Asian (EAS) AF: 0.00209 AC: 83 AN: 39694

South Asian (SAS) AF: 0.147 AC: 12624 AN: 86018

European-Finnish (FIN) AF: 0.193 AC: 10311 AN: 53328

Middle Eastern (MID) AF: 0.152 AC: 637 AN: 4182

European-Non Finnish (NFE) AF: 0.181 AC: 200181 AN: 1104254

Other (OTH) AF: 0.165 AC: 9911 AN: 59892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.160 AC: 24282 AN: 151546 Hom.: 2030 Cov.: 30 AF XY: 0.159 AC XY: 11773 AN XY: 74036

African (AFR) AF: 0.153 AC: 6320 AN: 41328

American (AMR) AF: 0.122 AC: 1850 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3464

East Asian (EAS) AF: 0.00503 AC: 26 AN: 5166

South Asian (SAS) AF: 0.138 AC: 658 AN: 4774

European-Finnish (FIN) AF: 0.205 AC: 2165 AN: 10542

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12235 AN: 67752

Other (OTH) AF: 0.147 AC: 310 AN: 2102

Alfa AF: 0.169 Hom.: 717

Bravo AF: 0.151

EpiCase AF: 0.172

EpiControl AF: 0.173

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.87
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4963051; hg19: chr11-1264965; COSMIC: COSV71589888; COSMIC: COSV71589888;